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US Food and Drug Administration (FDA) Commissioner Margaret Hamburg

Pay attention, as I can’t say this seriously enough. Last week, the FDA took a drug off the market, and the reasons should send shivers of fear down the backs of consumers, investors, generic drug companies – and the FDA.

The FDA announced last week that the 300mg generic version of Wellbutrin XL manufactured by and marketed by Teva Pharmaceuticals was being recalled because it did not work. And this wasn’t just a problem with one batch – this is a problem that has been going on with this particular drug for four or five years, and the FDA did everything it could to ignore it.

The FDA apparently approved this drug – and others like it – without testing it. The FDA just assumed if one dosage strength the drug companies submitted for approval works, then the other higher dosages work fine also. With this generic, American consumers became the FDA’s guinea pigs to see if the FDA's assumption was right. It wasn't.

Background

In December 2006, the first generic versions of the popular anti-depressant Wellbutrin XL were approved by the FDA. The drug comes in two dosage strengths, 150 milligrams and 300mg. The 300mg dose is generally used for patients with more severe depression and anxiety and patients who don’t respond to the lower dose. The FDA approved generic versions of both dosage strengths from a few generic drug companies: Teva Pharmaceuticals (manufactured by Impax Laboratories and marketed by Teva Pharmaceuticals), Anchen, Actavis, and Pharmaceuticals. Almost immediately, the FDA started receiving reports from patients that claimed the 300mg dose was being associated with side effects and reduced efficacy.

The People’s Pharmacy, a well-known syndicated radio and newspaper columnist husband and wife team, notified the FDA that hundreds of patients had logged their own complaints of side effects with the then-recently approved generic version of Wellbutrin XL. The FDA brushed off the People’s Pharmacy and others that raised the issue, stating that they had faith that the drugs were equivalent and that perhaps the patients, who had mental disease, were more prone to perceived problems with a change in the medication than others. This was seen by many as essentially telling patients “it’s all in their head.” After several more years and public outcry, the FDA was forced to take action.

What Action Did The FDA Take?

Instead of doing its own study on the drug, the FDA asked the drug maker to conduct a study to determine whether the generic drug was equivalent to the brand. The FDA, in their recent press release, claims that Teva started the trial but later abandoned it because of slow patient enrollment. It was already 2010, several years after knowing there was a problem, the FDA was forced to do its own study.

The FDA study was completed in August 2012 – more than 5 years after the initial problems were reported. The FDA study showed that the 300mg dose from Teva is ineffective insomuch as it did not deliver enough of the drug.

Oddly, despite the result being available in August 2012, the public was only made aware of this in October 2012.

How Did This Happen?

When the FDA issued its press release on October 3rd, it said that the FDA made a mistake in that it had taken the data for the 150mg version. Since that dosage had worked fine, the FDA just assumed that the 300mg dosage would work. I am not joking – they indicated that this case caused them to change the way they do things. They approved the drugs by extrapolating the data for the 150mg, assuming the 300mg works the same.

Clearly, the FDA has serious doubts on how they approved the 300mg dosages by just assuming if the 150mg works then the 300mg must work also. The FDA’s press release makes that clear:

FDA has approved five generic versions of Wellbutrin XL 300 mg. Each of these generics was approved based on bioequivalence studies comparing the 150 mg strength of the products to Wellbutrin XL 150 mg. Studies were not performed directly on the 300 mg strength of the products. Rather, the bioequivalence studies were performed using the 150 mg strength, and the results were extrapolated to establish bioequivalence of the 300 mg product.

FDA has determined that this approach is no longer appropriate to establish bioequivalence of 300 mg bupropion hydrochloride extended-release tablets to Wellbutrin XL 300 mg, and the Agency is revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products.

This cleverly worded press release hides the fact that this method of approving Wellbutrin XL or any drug is not only “no longer” appropriate, but was never an appropriate way of approving drugs. Just extrapolating data is an erroneous assumption and ignores basic principles known by most high school science students. In addition, if you don’t test the larger dosages, what if drug companies simply submitted 300mg drugs that had no drug in them? That seems like more than just a moronic mistake, but a dangerous approach to approving drugs.

But What About The Other Generics The FDA Approved?

Instead of immediately pulling the drugs that were approved with the same faulty approach and instead of the FDA doing their own bioequivalence studies, the FDA has asked the other generic drug companies to do these tests for the FDA and submit these results by March 2013. The idea of a regulatory agency turning over the testing process of a drug to the drug companies when there is doubt about their safety and efficacy seems like it is giving up its role of independent oversight of the companies it has regulatory power over.

It seems more appropriate that the FDA conduct these tests and, since the safe brand drug remains on the market, to immediately remove the other generics while we await the results of the testing.

The FDA has long been a strong proponent of generic drugs, and generics have saved consumers and the federal government billions of dollars vs. brand-name drugs. Many consumers incorrectly believe that a brand drug is identical to the generic drug, and even the FDA on its website calls generics “identical." Generic drug companies are subject to FDA inspections just like their name brand counterparts, but the drugs themselves do not need to be identical to the brands; they need to be "bioequivalent" and are given leeway on how close to the brand they need to be. To me, it’s similar to how Cheerios are almost like the store brand of toasted oat cereal – “Cheery-O’s” – very similar, but not the same. Roughly speaking, "bioequivalent" means they need to show that the drug releases an active ingredient in nearly the same, but not exact, concentration as the brand.

The whole system works if the generics are bioequivalent, and to ensure that they are, most consumers believe that the FDA would test to see if the generics being considered for approval work as promised. It appears that many approved generic drug versions have not even been subject to independent FDA studies.

But how could the FDA know if a drug is bioequivalent if it doesn't even test it? It can't.

How This is A Safety Issue

The lack of efficacy for a high dose anti-depressant is really a safety issue, not a manufacturing issue.

How many patients who were not adequately treated on the 150mg dose were put on the 300mg only to see their symptoms get worse because the generic did not work as promised? How many patients, doctors, and their families thought that this was simply a further deterioration of a patient’s condition and mental state? How many parents had to worry about their children when their anti-depressant seemed to stop working? How many people committed suicide taking a generic antidepressant that did not work?

And the appalling part of all this is that the fact that this could have been prevented if the FDA had simply tested the drug before they approved it, or at the least heeded the hundreds of complaints.

8 Immediate Steps That Should Be Taken

Here are eight steps that should be taken immediately to address this crisis and the underlying issues that caused it:

The FDA should immediately suspend approvals for generics Wellbutrin XL and advise doctors via a Dear Doctor Letter to switch to the brand. Pending confirmatory studies, suspend approvals of the other generics. It is clear if the FDA is asking manufacturers to do new studies on these drugs, it does not 100% trust its effectiveness and safety. The FDA should not keep drugs on the market where it cannot stand by the efficacy and safety of the drug when the brand is readily available

The FDA should conduct their own study of the bioequivalence of the other generic Wellbutrin XL it approved and not rely on the drug makers.

The FDA should immediately conduct a review of all generic drug approvals in this class and others to determine what other approvals were made with the same faulty approach of assuming that if one dose worked then the higher dose or lower dose must work the same. Since the FDA has now abandoned this faulty procedure because it resulted in ineffective drugs being put on the market, then it should re-review all these previous approvals.

The FDA should conduct a thorough study of how the vigilance system of early warnings and warnings from others such as the People’s Pharmacy went unheeded for more than 5 years.

The FDA should undertake the difficult but important step of researching which patients took the 300mg generic, which ones may have attempted or committed suicide while on the 300mg or shortly after being switch from the ineffective. Research how many institutionalized patients are on the 300mg dose – advise they are switched to the brand immediately. The families of these patients should know why the drugs they trusted to work didn’t.

The FDA should tighten the regulations for bioequivalence for narrow therapeutic window drugs, especially those that pharmacists and patients have already complained about not working.

The FDA should provide consumers with the timeline and all correspondence and phone records surrounding this case to show why a two month delay would take place from knowing the drug did not work to telling the public.

Congress should convene an oversight committee on how this happened and what it means for drug safety. Was there anyone at the FDA during this or previously that had issue with the “if the 150mg works, then assume the 300mg works too” approach?

The FDA Commissioner Peggy Hamburg needs to answer for this. When you keep score by loved ones’ worry and by patient lives cut short by suicide, this is not just the tale of a simple recall, but of a failure of the system and sign of dangerous incompetence.

Note: An earlier version of this posting identified the recalled product as being from Teva Pharmaceuticals. For greater clarification, we have noted that the generic drug subject to the FDA action is manufactured by Impax Laboratories and marketed by Teva Pharmaceuticals